CD43 is a cell-surface protein expressed in various hematoblasts except erythrocytes. A human CD43, known as sialophorin or leukosialin, is composed of a mucine-like extracellular domain consisting of 235 amino acids, a transmembrane domain consisting of 23 amino acids, and an intracellular domain consisting of 123 amino acids, and the relevant genetic information is encoded in one exon. There are many serine (46 residues) and threonine (47 residues) amino acids in the human extracellular CD43 domain, and most of them possess O-linked glycan (O-glycan). Additionally, N-glycan is also linked to CD43. The structure of O-glycan is known to vary greatly depending on the cell type. CD43 has an intron consisting of 378 base pairs, which divides the exon into two, and the entire transcript material information is encoded in the second exon.
CD43 is synthesized as a precursor of about 40 kDa including N-glycan, and is converted to a material of 115 kDa to 200 kDa through a consecutive mature glycosylation processes. The strictly-controlled glycosylation process after transcription forms characteristic molecular weight isoform proteins depending on the type and these can be expressed differently depending on the cell type.
The glycosylated epitope of CD43 has been known as a specific marker restricted to white blood cells, and its specific utility as a marker for hematologic malignancy has been revealed. For this reason, in many studies, the possibility of using antibodies binding to the glycosylated epitope of CD43 for diagnostic or therapeutic purposes has been explored. The rodent monoclonal antibody recognizing CD43 has been known to induce apoptosis in lineage marker-negative bone marrow hematopoietic progenitor cells that over-express CD34 (Bazil et al. (1996) Blood, 87(4):1272-81) and human T-lymphoblastoid cells (Brown et al. (1996) J. Biol. Chem. 271:27686-95). However, these antibodies are not effective for detecting or treating cancer cells, since most of them react with the glycosylated epitope located in the CD43 extracellular domain expressed in mature (non-cancerous) hematopoietic cells. Therefore, it is required to develop a more improved material binding to the glycosylated epitope of CD43 for diagnosing, tracing and treating hematologic malignancy.
On the other hand, the cancer stem cell hypothesis, which suggests abnormal stem cells are involved in the occurrence and recurrence of cancer in a hierarchical model, has been known.
All tissues of human body are originated from organ-specific stem cells. The organ-specific stem cells have the ability of self-renewal and differentiation into all cells composing each organ. These organ-specific stem cells are distinguished from embryonic stem cells in that they can only be differentiated into cell types in the specific organ.
The cancer stem cell hypothesis largely consists of two elements. First, the tumor occurs in a stem cell in the tissue, and second, the tumor occurred from the stem cell has basic properties of stem cells.
The cancer stem cell as a cancer cell having a limitless regenerative ability, defined as a cell which can effectively produce tumor when injected into an immune-suppressed mice, and express its unique heterogeneity which the primary tumor possesses well in the formed tumor.
The cancer stem cell hypothesis has become more materialized as the stem cell biology has been recently developed. The cancer stem cell hypothesis took a step forward by the report that human leukemia was reproduced in an immunosuppressed mouse grafted possible cancer stem cells from an acute myelocytic leukemia patient in 1997 (Bonnet D, Dick JE; Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730-7).
The various heterogeneity that a malignant tumor exhibits corresponds to the various differentiation potential of stem cells, and the repeatedly occurring drug resistance of cancer cell, despite of a number of target treatments also corresponds to the basic property of stem cells. As the cancer stem cell could form a new tumor mass by self-renewal, even though tumor cells other than cancer stem cells are completely removed by surgery and the chemotherapy, if the cancer stem cell is remained, the cancer becomes recurred again.
Therefore, in order to cure the cancer completely, it is required to develop a technology to inhibit or remove the cancer stem cell.